靶向人β-淀粉样蛋白的多功能纳米抑制剂的合成、筛选及其对阿尔茨海默症治疗机制的研究

Alzheimer’s disease (AD) is the most common form of dementia, which affects more than 24 million people worldwide. Although the molecular mechanisms of AD pathogenesis are not clearly understood owing to its complexity, recent advances have demonstrated that the polymerization of amyloid β-peptides (Aβ) into amyloid fibrils is crucial. Therefore, the development of Aβ aggregation inhibitors has received much attention in the therapeutic and preventive treatment of AD. However, though organic small molecule and peptide inhibitors have achieved some effects, they still have obvious defects, such as poor targeting, high toxicity, cannot through the blood-brain barrier and so on. This project focuses on the construction of a series of nanoparticle inhibitors with “target”, “vector” and “treatment” together, which are not owned by the existing inhibitors. Then the experimental and computer-aided methods are combined to establish an inhibition model, which can be applied for further research on AD pathogenesis, the way for prevent and treat AD and exploring the interaction between functional nanoparticles and organic biomolecules.

阿尔茨海默病（Alzheimer's disease，AD），又称老年痴呆症，是现代社会中人类健康的第四大杀手。越来越多的证据表明，过量的β-淀粉样蛋白（β-amyloid peptide，Aβ）的产生和聚集在AD的发病过程中起着核心作用，因此设计相应的Aβ抑制剂就成为了化学和生物学领域的研究前沿及热点。尽管目前已报道的有机小分子和肽类抑制剂虽已取得了阶段性进展，但仍然存在着靶向性差、毒性高、无法通过血脑屏障等明显缺陷。本项目针对Aβ的特殊氨基酸序列，提出了以纳米粒子为基本骨架设计并合成一系列集“靶向”、“载体”和“治疗”于一身的“多功能纳米抑制剂”的研究方案，这类抑制剂具有靶向性好、易于穿透血脑屏障、毒副作用小和几乎没有免疫排斥反应等优势，可以有效弥补现有抑制剂的不足。为日后进一步研究AD的发病机理、预防与治疗以及研究功能化纳米粒子-有机生物分子间的相互作用探索有效的途径。

阿尔茨海默症（Alzheimer's disease，AD），又称老年痴呆症，是现代社会中人类健康的第四大杀手。现代医学及分子生物学研究表明，β-淀粉样蛋白（β-amyloid peptide，Aβ）的产生、聚集、沉淀以及其他相关毒副产物与AD 的发生、发展密切相关。因此设计相应的多功能Aβ靶向治疗剂就成为了化学和生物学领域的研究前沿及热点。截止目前虽然已经陆续报道了一些有机小分子和肽类抑制剂具备了部分的治疗功能，但是这些治疗剂普遍存在治疗功效单一、靶向性差、毒性高、无法通过血脑屏障等明显缺陷。因此本项目针对Aβ的特殊氨基酸序列，利用部分研究较为成熟的纳米粒子为前体，设计并合成一系列靶向Aβ的多功能AD纳米复合治疗剂。这类治疗剂普遍具有靶向性好、多功能、易于穿透血脑屏障、毒副作用小和几乎没有免疫排斥反应等优势，可以有效弥补现有治疗剂的不足。为日后进一步研究AD的发病机理，预防和治疗AD探索一条有效的途径。